Engineered Source-Specific Extracellular Vesicles for Neurodegenerative Diseases: From Biological Barriers to...

With the rapidly aging global population, neurodegenerative diseases (NDDs) present an escalating challenge to public health. The complex, self-perpetuating pathological network of NDDs, encompassing aberrant protein aggregation, chronic neuroinflammation, synaptic impairment, and mitochondrial dysfunction, significantly impedes the efficacy of traditional single-target pharmacological interventions. Extracellular vesicles (EVs), which encapsulate a diverse array of functional cargoes, including proteins, lipids, and nucleic acids, mediate both horizontal intercellular communication and cross-kingdom signaling. Their distinctive biological properties-characterized by low immunogenicity, favorable biocompatibility, and an intrinsic ability to cross the blood-brain barrier (BBB)-position EVs as a promising multi-target pharmacological platform for treatment of NDDs. By integrating genetic, chemical, and physical engineering strategies, these vesicles have been redefined as programmable nanotherapeutic tools. To address the cost and scalability constraints associated with mammalian cell-derived EVs, plant-derived EV-like nanoparticles (PDENs) represent a promising "green" platform. In this review, we systematically delineate the pathological mechanisms of NDDs, the diverse sources and characteristics of EVs, their functionalization via advanced engineering, and their multifaceted applications in NDDs therapy. Finally, we discuss the translational potential of these platforms, particularly their capacity to address the challenges associated with BBB penetration, and outline a framework to guide the development and clinical evaluation of EV-based therapies for NDDs.